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First published online February 7, 2007
doi: 10.1242/10.1242/jcs.03385

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Decoding ubiquitin sorting signals for clathrin-dependent endocytosis by CLASPs

¹ Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, PA 15261 USA
² Program in Cell and Lung Biology, Hospital for Sick Children Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada

^* Author for correspondence (e-mail: traub{at}pitt.edu; glucas{at}sickkids.ca)

Accepted 2 January 2007

Cargo selectivity is a hallmark of clathrin-mediated endocytosis. A wide range of structurally unrelated internalization signals specify the preferential clustering of transmembrane cargo into clathrin coats forming on the plasma membrane. Intriguingly, the classical endocytic adaptor AP-2 appears to recognize only a subset of these endocytic sorting signals. New data now reveal the molecular basis for recognition of other internalization signals, including post-translationally appended ubiquitin, by clathrin-coat-associated sorting proteins (CLASPs). Curiously, structurally related ubiquitin-recognition modules are shared by select CLASPs and the 26S proteasome, and recent work indicates that both display similar requirements for ubiquitin binding. During endocytosis, these modules engage oligoubiquitylated cargo in the form of polyubiquitin chains and/or multiple single ubiquitin molecules appended to different acceptor lysines. Functional separation between clathrin-mediated endocytosis and proteasome-dependent proteolysis is probably ensured by temporally regulated, local assembly of ubiquitin-tagged membrane cargo at sorting stations on the cell surface, shielding ubiquitin sorting signals from the proteasome. Thus, an expanded repertoire of CLASPs couples the process of clathrin-coat assembly with high-fidelity incorporation of assorted, cargo-specific sorting signals.

Key words: Clathrin, Cargo sorting, Ubiquitin, Adaptor, CLASP

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